Announcement • May 21
Alterity Therapeutics Announces Data Presentations Supporting Advancement Of ATH434 Into Phase 3 In Multiple System Atrophy
Alterity Therapeutics announced that presentations related to the Company’s development program in Multiple System Atrophy (MSA) were delivered at three medical conferences showcasing Alterity’s novel imaging and biomarker approach, promising Phase 2 data, and current plans to advance ATH434 into Phase 3 clinical development. Quantitative Susceptibility Mapping Detects Progressive Iron Accumulation in Early MSA: New research shows that Alterity’s MRI imaging approach can detect MSA in its earliest stages and track brain iron changes over time, a methodology that could transform how MSA trials are run. Dr. Trujillo presented findings recently published in NeuroImage demonstrating that quantitative susceptibility mapping (QSM) detects progressive iron accumulation in MSA. The measure may serve as a biomarker for early diagnosis, monitoring, and trial enrichment. The evaluation utilizes longitudinal data generated through Alterity’s Biomarkers of Progression in Multiple System Atrophy (bioMUSE) Natural History Study, together with additional cross-sectional MSA, Parkinson’s Disease, and healthy control data. QSM provides the ability to: detect iron dysregulation early — even before clinical diagnosis, track progression over 12 months, provide individual-level, interpretable maps for monitoring, and it is standardizable across scanners which can provide a meaningful tool for multicenter trials. Results from a Randomized, Double-Blind, Placebo-Controlled Study of ATH434 in MSA using CSF NfL as a Covariate: A new analysis of Alterity’s Phase 2 trial brings together clinical, biomarker, and imaging evidence that support ATH434’s impact on slowing MSA progression. Dr. Claassen’s poster described outcomes from the ATH434-201 Phase 2 clinical trial in MSA. In particular, the poster evaluates CSF NfL1 which is an established prognostic biomarker of clinical decline in MSA and was prespecified as a disease-severity covariate in the trial. There were several key outcomes: 1) ATH434 slowed functional decline in MSA: Significant effect at 50 mg BID (-4.0 points, p=0.035; ~48% slowing) and a consistent directional trend at 75 mg BID. Combined active arms significantly slowed UMSARS2 I progression vs placebo (p=0.047). 2) CSF NfL is a meaningful prognostic covariate: Higher baseline CSF NfL predicted greater UMSARS-I worsening (ß=0.90, p=0.033). Adjusting for it strengthened detection of treatment effects and supports CSF NfL for stratification in future trials. 3) Imaging supports the iron-chaperone mechanism: QSM trend of reduced iron accumulation in putamen and globus pallidus consistent with the iron-chaperone mechanism of action; the dentate signal increase is consistent with glymphatic iron redistribution rather than disease progression. 4) ATH434 is a promising potential disease-modifying therapy: Convergent clinical, biomarker, and imaging signals support continued development. ATH434 Clinical Update and Phase 3 Planning: New analyses of Alterity’s Phase 2 trial were presented, bringing together clinical, biomarker, and imaging evidence that support ATH434’s impact on slowing MSA progression. In particular, analyses of key clinical endpoints, including the Unified MSA rating scale Part I, were presented that include CSF NfL as a covariate. The biomarker data presented by Dr. Stamler included QSM MRI data from the ATH434-201, demonstrating that ATH434 decouples iron accumulation from clinical progression thus supporting its role as an iron chaperone. New data on the impact of ATH434 on swallowing were also presented, demonstrating that both doses of ATH434 reduce the progression of this key MSA symptom. Swallowing impairment was assessed with the 15-item Swallowing Disturbance Questionnaire (SDQ), a validated patient reported outcome. Over 52 weeks treatment, placebo patients worsened by a mean adjusted increase score of 8.5 points as compared to an increase of 1.2 and 5.0 points for the 50 mg and 75 mg groups, respectively, with the mean adjusted difference at 50 mg achieving statistical significance (p=0.003). Alterity’s lead candidate, ATH434, is an oral agent designed to reduce iron accumulation and inhibit abnormal protein aggregation associated with neurodegeneration. ATH434 has been shown to reduce a-synuclein pathology and preserve neuronal function by restoring normal iron balance in the brain in preclinical models. As an iron chaperone, it has excellent potential to treat Parkinson’s disease as well as various Parkinsonian disorders such as Multiple System Atrophy (MSA). Positive results from the randomized, double-blind, placebo-controlled Phase 2 clinical trial in patients with MSA demonstrated robust clinical efficacy, target engagement as indicated by key biomarkers, and a favorable safety profile. Positive data from a second Phase 2 open-label biomarker trial in patients with more advanced MSA reinforced these results. ATH434 has been granted Fast Track Designation by the U.S. Food and Drug Administration (FDA), and Orphan Drug Designation by the FDA and the European Commission for the treatment of MSA. The ATH434-201 Phase 2 clinical trial is a randomized, double-blind, placebo-controlled investigation of 12 months treatment with ATH434 in patients with MSA. The study evaluated the efficacy, safety and pharmacokinetics of ATH434 as well as the effect of ATH434 on neuroimaging and protein biomarkers. Wearable sensors were employed to evaluate motor activities outside of the clinic. The study enrolled 77 adults who were randomly assigned to receive ATH434 50 mg or 75 mg twice daily or matching placebo. The data showed that, compared to placebo, ATH434 produced clinically and statistically significant improvement on the modified Unified Multiple System Atrophy Rating Scale (UMSARS) Part I, a functional rating scale that assesses disability on activities of daily living affected in MSA. Additional efficacy assessments demonstrated improvement consistent with the positive UMSARS Part I findings including trends in improved motor performance on the Parkinson’s Plus rating scale, the Clinical Global Impression of Severity Scale, and the Orthostatic Hypotension Symptom Assessment (a patient reported outcome). Wearable sensor data indicated that ATH434 also led to increased activity in an outpatient setting. Biomarkers were used to evaluate potential drug effect and target engagement relative to placebo. Both dose levels reduced iron accumulation in MSA affected brain regions with trends in preservation of brain volume. ATH434 was well tolerated with similar adverse event rates compared to placebo and no serious adverse events attributed to ATH434. Additional information on the Phase 2 trial can be found by ClinicalTrials.gov Identifier: NCT05109091. Biomarkers of progression in Multiple System Atrophy (bioMUSE) is a natural history study that aims to track the progression of individuals with MSA, a parkinsonian disorder without an approved therapy.